Impact of intra-tumoral immunity on predicting response and survival after neoadjuvant cisplatin-based chemotherapy in patients with muscle invasive bladder cancer.

Publication Title

Cancer Med

Authors

Alberto Mendoza-Valderrey, Translational Cancer Immunology and Immunotherapy Department, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USAFollow
Jane Choe, Department of Urologic Oncology, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA.Follow
Daria Kessler, Bioinformatic Department, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USAFollow
Gianna Jimenez, Department of Urologic Oncology, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USAFollow
Xinmin Li
Steven E Kolker, Pathology Department, Providence Saint John's Health Center, Santa Monica, California, USAFollow
Warren M Allen, Pathology Department, Providence Saint John's Health Center, Santa Monica, California, USAFollow
Jennifer M Linehan, Department of Urologic Oncology, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USAFollow
Przemyslaw W Twardowski, Department of Urologic Oncology, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USAFollow
Maria Ascierto, Translational Cancer Immunology and Immunotherapy Department, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USAFollow

Document Type

Article

Publication Date

8-1-2024

Keywords

oregon; portland; psvmc; Humans; Urinary Bladder Neoplasms; Cisplatin; Male; Female; Neoadjuvant Therapy; Aged; Tumor Microenvironment; Middle Aged; Neoplasm Invasiveness; Cystectomy; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Prognosis; Neutrophils

Abstract

Background: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Pathologic complete response (pCR) is associated with favorable outcomes, but only 30%-40% of patients achieve that response. The aim of this study is to investigate the role played by the Tumor and Immune Microenvironment (TIME) in association with the clinical outcome of patients with MIBC undergoing NAC.

Methods: Nineteen patients received NAC and were classified as pCR (n = 10) or non-pCR (n = 9). Bulk RNA-seq and immune protein evaluations using Digital Spatial Profiling (DSP) were performed on formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before NAC (baseline). Immunohistochemistry (IHC) evaluation focused on CD3 and CD20 expression was performed on baseline and end-of-treatment (EOT) FFPEs. Baseline peripheral blood was assessed for lymphocyte and neutrophil counts. Kaplan-Meier analyses and Cox PH regression models were used for survival analyses (OS).

Results: In the periphery, pCR patients showed lower neutrophil counts, and neutrophil/ lymphocyte ratio (NLR) when compared to non-pCR patients. In the tumor microenvironment (TME), gene expression analysis and protein evaluations highlighted an abundance of B cells and CD3+ T cells in pCR versus non-pCR patients. On the contrary, increased protein expression of ARG1+ cells, and cells expressing immune checkpoints such as LAG3, ICOS, and STING were observed in the TME of patients with non-pCR.

Conclusions: In the current study, we demonstrated that lower NLR levels and increased CD3+ T cells and B cell infiltration are associated with improved response and long-term outcomes in patients with MIBC receiving NAC. These findings suggest that the impact of immune environment should be considered in determining the clinical outcome of MIBC patients treated with NAC.

Keywords: biomarkers; bladder cancer; digital pathology; neoadjuvant.

Clinical Institute

Neurosciences (Brain & Spine)

Specialty/Research Institute

Neurosciences

Specialty/Research Institute

Pharmacy

DOI

10.1002/cam4.70088